WO2008018692A1 - Novel chalcone derivatives which inhibit the il-5 activity - Google Patents

Novel chalcone derivatives which inhibit the il-5 activity Download PDF

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WO2008018692A1
WO2008018692A1 PCT/KR2007/003281 KR2007003281W WO2008018692A1 WO 2008018692 A1 WO2008018692 A1 WO 2008018692A1 KR 2007003281 W KR2007003281 W KR 2007003281W WO 2008018692 A1 WO2008018692 A1 WO 2008018692A1
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mmol
hydrogen
compound
chalcone derivatives
cells
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Sang-Hun Jung
Hyun-Mo Yang
Hye-Rim Shin
Youngsoo Kim
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The Industry And Academic Cooperation In Chungnam National University (Iac)
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/32—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing keto groups
    • C07C65/40—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing keto groups containing singly bound oxygen-containing groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/94—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of polycyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/45—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by at least one doubly—bound oxygen atom, not being part of a —CHO group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/30—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms
    • C07C233/33—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
    • C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/72—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups
    • C07C45/74—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups combined with dehydration
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/82—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups
    • C07C49/835—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups having unsaturation outside an aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/84—Ketones containing a keto group bound to a six-membered aromatic ring containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/86—Ketones containing a keto group bound to a six-membered aromatic ring containing —CHO groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
    • C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to novel chalcone derivatives, a preparation method thereof and the use thereof as interleukin-5 (IL-5) inhibitors, and more particularly to novel chalcone derivatives, which are low-molecular nonpeptide substances as IL-5 inhibitors having the effect of treating chronic allergic inflammation, as well as a preparation method thereof.
  • IL-5 interleukin-5
  • allergic diseases include bronchial asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, urticaria and the like. Allergic diseases occurring at a very high incidence mostly takes a chronic course, there is no suitable method for treating them. For this reason, allergic diseases cause serious problems, including pain and economic loss. Thus, in the USA NIH, allergic diseases were classified as one of five major diseases to be overcome in the 21th century.
  • Allergy is a hypersensitive disease that involves inflammatory responses.
  • the inflammatory responses which occur after repeated exposure to antigens, occur due to the complex interaction between inflammation-related cells (such as mast cells, eosinophils and Th2 cells) and structural cells such as vascular endothelial cells, fibroblasts and epithelial cells.
  • inflammation-related cells such as mast cells, eosinophils and Th2 cells
  • structural cells such as vascular endothelial cells, fibroblasts and epithelial cells.
  • antigens are taken up and processed by antigen-presenting cells such as macrophages, and then displayed on the surface of APC (antigen-presenting cells).
  • APC antigen-presenting cells
  • T cells having antigens presented by APC secrete cytokines such as interleukin-4 (IL-4) to activate B cells, which then produce antibody IgE.
  • IL-4 interleukin-4
  • the produced IgE binds to mast cells having an IgE receptor on the surface thereof.
  • mast cells are activated to release chemical substances, such as histamine, prostaglandin (PG) and leukotriene (LT), thus causing disease symptoms.
  • PG prostaglandin
  • LT leukotriene
  • Th2 cells exposed to antigens release cytokines, such as IL-5, IL-3 and
  • IL-5 plays an important role in allergic responses, because it increases the differentiation of bone marrow cells into eosinophils, increases the adhesion of eosinophils to endothelial cells to increase the migration of eosinophils to the target organ, inhibits the apoptosis of eosinophils and also activates eosinophils.
  • the activated eosinophils release toxic proteins, such as major basic protein (MBP) and eosinophil cationic protein (ECP). These toxic proteins induce lipid mediators, cytokines and chemokines to cause hypersensitivity, so that the epithelial cells in the target organ are detached.
  • MBP major basic protein
  • ECP eosinophil cationic protein
  • an allergy therapeutic agent which can control the physiological activity of IL-5, is a low-molecular nonpeptide substance and, and the same time, has selectivity to IL-5 and inhibitory activity against IL-5.
  • the present inventors reported novel chalcone derivatives, which are low-molecular nonpeptide substances having an IL-5 inhibitory effect, as well as a preparation method thereof (Korean Patent Registration No. 541222). Then, the present inventors have continued to conduct studies to compounds having greater effects and, as a result, discovered novel chalcone derivatives, which are more effective as IL-5 inhibitors, as well as a preparation method thereof.
  • the present invention has been made in order to solve the above-described problems occurring in the prior art, and it is an object of the present invention to provide novel compounds, which are low-molecular nonpeptide substances having selectivity to IL-5 and inhibitory activity against IL-5, as well as a preparation method thereof. [12] Another object of the present invention is to provide IL- 5 inhibitors comprising said compounds. [13]
  • the present invention provides novel chalcone derivatives represented by Formula 1 below, a preparation method thereof and the use thereof as IL- 5 inhibitors.
  • R is benzyl, arbitrary substituted benzyl, cyclohexylmethyl, arbitrary substituted cyclohexylmethyl, hydrogen, methyl or ethyl
  • R is benzyl, arbitrary substituted benzyl, cyclohexylmethyl, arbitrary substituted cyclohexylmethyl, hydrogen, methyl or ethyl
  • R is methoxy or hydrogen
  • R is Cl, -NHCOCH , -COOCH
  • novel chalcone derivatives represented by Formula 1 according to the present invention are effective as asthma control agents, which inhibit the introduction of eosinophils (that are major inflammation cells in the asthma response) into the airway and increase airway hypersensitivity to alleviate asthma and as inflammation inhibitors.
  • novel chalcone derivatives according to the present invention are low-molecular nonpeptide substances, they have no nonspecific response to proteins, unlike the prior known agents for treating allergic inflammation, and thus will be useful as allergy inhibitors.
  • the compounds of Formula 1 can be prepared by condensing a compound (A) with a compound (B) in an alcohol solvent in the presence of a base.
  • R R R and R are the same as defined in Scheme 1.
  • the alcohol solvent a C -C lower alcohol is preferably used, and as the base, sodium hydroxide or potassium hydroxide is preferably used.
  • the novel chalcone compounds all showed an inhibitory effect of 80% at a concentration of 50 ⁇ M and mostly showed a high inhibitory effect of more than 99%.
  • the chalcone compounds disclosed in Korean Patent Registration No. 541222 having an IC value more than lO ⁇ M
  • the chalcone compounds of the present invention showed an IC value of less than 5 ⁇ M, suggesting that the inventive compounds had more excellent IL-5 inhibitory effects.
  • the chalcone compounds of the present invention can be used as IL-5 inhibitors.
  • a composition containing the chalcone compounds can be prepared according to a conventional method and may be formulated alone or in combination with pharmaceutically acceptable carriers, excipients, diluents and so on, to prepare formulations, such as powders, granules, tablets, capsules, injections, and the like.
  • these compounds may be formulated unit dosage formulations or multiple dosage formulations for oral or parenteral administration, such that they can be used as therapeutic agents having IL-5 inhibitory effects.
  • Example 8 ( ⁇ V4-r3-(2-cyclohexylmethoxy-6-hydroxyphenylV3-oxopropene-l-yll bezensulfonamide
  • Example 15 ( ⁇ V3-(4-chlorophenylV l- ⁇ . ⁇ -diethoxyphenyDpropenone [79] Under the same conditions as in Example 1, 0.1 g (0.56 mmol) of
  • 2,6-diethoxyacetophenone was condensed with 0.080 g (1.43 mmol) of benzaldehyde, thus preparing 0.129 g of compound 19 (Table 1).
  • Example 21 (EV l-(7 A ⁇ -trimethoxyphenyiyS- ⁇ -nitrophenyPpropenone
  • Y16 cells used in the experiment are floating cells that proliferate in media.
  • Y16 cells were diluted in RPMI- 8% FBS medium to a cell concentration of 1 x 10 cells/D, and 1 ml of the medium was dispensed into a Petri dish. Then, 9 D of RPMI- 8% FBS medium and 5 U/D of mIL-5 were added thereto, and then the mixture was cultured in 5% CO at 37 0 C for 48 hours. The culture medium was centrifuged at 4 0 C and 1500 rpm to precipitate the cells, and the cells were suspended in 1 D of medium, stained with trypan blue and then counted.
  • Y16 cells were dispensed into each well of a 96- well microplate at a cell concentration of 1 x 10 cells/D, and 50 D of mIL-5 and 50 D of each sample were added to each well.
  • mIL-5 and the sample solutions were diluted in RPMI-8% FBS medium before use, and in a control A group, medium was added instead of the sample. In a control B group, medium was added instead of IL-5 and the sample.
  • the cell media thus prepared were cultured in the same conditions as in the above section 3), and then measured for absorbance.
  • sample absorbance at 450nm of sample group
  • control A 450 absorbance at 450nm of control A g ⁇ rouxp-
  • control B 450 absorbance at 450nm of control B g orourp [121] [table 1] [122]
  • novel chalcone derivatives according to the present invention will be useful as asthma control agents for alleviating asthma symptoms, inflammation inhibitors, and allergy inhibitors having no nonspecific response to proteins.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
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Abstract

Disclosed herein are novel chalcone derivatives, which are low-molecular nonpeptide substances as interleukin-5 (IL-5) inhibitors having the effect of treating chronic allergic diseases, as well as a preparation method thereof and the use thereof as IL-5 inhibitors. Because the novel chalcone derivatives are low-molecular nonpeptide substances, they have no nonspecific response to proteins, unlike the prior known agents for treating allergic inflammation, and thus will be useful as allergy inhibitors.

Description

Description NOVEL CHALCONE DERIVATIVES WHICH INHIBIT THE IL-
5 ACTIVITY Technical Field
[1] The present invention relates to novel chalcone derivatives, a preparation method thereof and the use thereof as interleukin-5 (IL-5) inhibitors, and more particularly to novel chalcone derivatives, which are low-molecular nonpeptide substances as IL-5 inhibitors having the effect of treating chronic allergic inflammation, as well as a preparation method thereof.
[2]
Background Art
[3] As well known, allergic diseases include bronchial asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, urticaria and the like. Allergic diseases occurring at a very high incidence mostly takes a chronic course, there is no suitable method for treating them. For this reason, allergic diseases cause serious problems, including pain and economic loss. Thus, in the USA NIH, allergic diseases were classified as one of five major diseases to be overcome in the 21th century.
[4] Allergy shows symptoms such as itching in the early allergic response and causes hypersensitive local inflammations due to detachment of the epithelial cells of the target organ in the late allergic response. In the prior art, cromoglycate developed as a membrane stabilizer, antihistamines, steroids and the like have been mainly used in clinical trials. In the case of asthma, bronchodilator adrenergic agonists (salmetrol, etc.), anticholinergic drugs (ipratropium, etc.), xanthine derivatives (theophylline, etc.) and the like have been used, but merely relieve symptoms and cannot achieve radical treatment.
[5] Allergy is a hypersensitive disease that involves inflammatory responses. The inflammatory responses, which occur after repeated exposure to antigens, occur due to the complex interaction between inflammation-related cells (such as mast cells, eosinophils and Th2 cells) and structural cells such as vascular endothelial cells, fibroblasts and epithelial cells.
[6] Specifically, antigens are taken up and processed by antigen-presenting cells such as macrophages, and then displayed on the surface of APC (antigen-presenting cells). T cells having antigens presented by APC secrete cytokines such as interleukin-4 (IL-4) to activate B cells, which then produce antibody IgE. The produced IgE binds to mast cells having an IgE receptor on the surface thereof. When the antibody binds to the antigen, mast cells are activated to release chemical substances, such as histamine, prostaglandin (PG) and leukotriene (LT), thus causing disease symptoms. Thus, acute allergic inflammation occurs.
[7] Meanwhile, Th2 cells exposed to antigens release cytokines, such as IL-5, IL-3 and
GM-CSF. In particular, IL-5 plays an important role in allergic responses, because it increases the differentiation of bone marrow cells into eosinophils, increases the adhesion of eosinophils to endothelial cells to increase the migration of eosinophils to the target organ, inhibits the apoptosis of eosinophils and also activates eosinophils. The activated eosinophils release toxic proteins, such as major basic protein (MBP) and eosinophil cationic protein (ECP). These toxic proteins induce lipid mediators, cytokines and chemokines to cause hypersensitivity, so that the epithelial cells in the target organ are detached. This causes chronic allergic inflammations such as bronchial asthma. Neutrophils are involved mainly in general inflammation, whereas eosinophils are involved mainly in allergic hypersensitive inflammation. Thus, it is well known that chronic allergic inflammation can be treated by inhibiting IL-5.
[8] In order to develop drugs for inhibiting eosinophils and IL-5, Schering-Plough
Corporation has conducted clinical trials for an allergy therapeutic agent using a human IL-5 monoclonal antibody, and Roche Inc. has synthesized IL-5-inhibiting isothiazolone derivatives (Devos et. al., Europ. J. Biochem., 1994, 225, 635), but there are limitations in developing medical drugs using these compounds, due to nonspecific responses to proteins other than IL-5.
[9] Thus, there is a need to develop an allergy therapeutic agent, which can control the physiological activity of IL-5, is a low-molecular nonpeptide substance and, and the same time, has selectivity to IL-5 and inhibitory activity against IL-5. Previously, the present inventors reported novel chalcone derivatives, which are low-molecular nonpeptide substances having an IL-5 inhibitory effect, as well as a preparation method thereof (Korean Patent Registration No. 541222). Then, the present inventors have continued to conduct studies to compounds having greater effects and, as a result, discovered novel chalcone derivatives, which are more effective as IL-5 inhibitors, as well as a preparation method thereof.
[10]
Disclosure of Invention Technical Problem
[11] The present invention has been made in order to solve the above-described problems occurring in the prior art, and it is an object of the present invention to provide novel compounds, which are low-molecular nonpeptide substances having selectivity to IL-5 and inhibitory activity against IL-5, as well as a preparation method thereof. [12] Another object of the present invention is to provide IL- 5 inhibitors comprising said compounds. [13]
Technical Solution
[14] To achieve the above objects, the present invention provides novel chalcone derivatives represented by Formula 1 below, a preparation method thereof and the use thereof as IL- 5 inhibitors.
[15] [formula 1]
[16]
Figure imgf000004_0001
[17] wherein, R is benzyl, arbitrary substituted benzyl, cyclohexylmethyl, arbitrary substituted cyclohexylmethyl, hydrogen, methyl or ethyl, R is benzyl, arbitrary substituted benzyl, cyclohexylmethyl, arbitrary substituted cyclohexylmethyl, hydrogen, methyl or ethyl, R is methoxy or hydrogen, R is Cl, -NHCOCH , -COOCH
3 , CH 2 OH, -CHO, -SO 2 NH 2 , -NO 2 , or -COOH
[18]
Advantageous Effects
[19] As described above, the novel chalcone derivatives represented by Formula 1 according to the present invention are effective as asthma control agents, which inhibit the introduction of eosinophils (that are major inflammation cells in the asthma response) into the airway and increase airway hypersensitivity to alleviate asthma and as inflammation inhibitors.
[20] Also, because the novel chalcone derivatives according to the present invention are low-molecular nonpeptide substances, they have no nonspecific response to proteins, unlike the prior known agents for treating allergic inflammation, and thus will be useful as allergy inhibitors.
[21]
Best Mode for Carrying Out the Invention
[22] Hereinafter, a method for preparing chalcone derivatives according to the present invention and the IL-5 inhibitory effects of the derivatives will be described in detail.
[23] (1) Preparation of novel chalcone derivatives
[24] As shown in Reaction Scheme 1 below, the compounds of Formula 1 can be prepared by condensing a compound (A) with a compound (B) in an alcohol solvent in the presence of a base. In the compound (A) and the compound (B), R R R and R are the same as defined in Scheme 1.
[25] [Scheme 1]
[26]
Figure imgf000005_0001
(A) (B)
[27] Herein, as the alcohol solvent, a C -C lower alcohol is preferably used, and as the base, sodium hydroxide or potassium hydroxide is preferably used.
[28] (2) Examination of IL-5 inhibitory effects
[29] The IL-5 inhibitory effects of the compounds obtained through the above-described process were examined.
[30] Using rat Y16 cells and IL-5, the absorbance of each sample was measured to determine mIL-5-dependent Y 16 proliferation indicative of the mIL-5 inhibitory effects of each compound. Inhibitory effects (%) at 50μM and IC values are shown in Table 1 below.
[31] As can be seen in Table 1, the novel chalcone compounds all showed an inhibitory effect of 80% at a concentration of 50μM and mostly showed a high inhibitory effect of more than 99%. In comparison with the chalcone compounds disclosed in Korean Patent Registration No. 541222, having an IC value more than lOμM, the chalcone compounds of the present invention showed an IC value of less than 5μM, suggesting that the inventive compounds had more excellent IL-5 inhibitory effects.
[32] As can be seen from the above results, the chalcone compounds of the present invention can be used as IL-5 inhibitors. In order for the chalcone compounds of the present invention to be used as therapeutic drugs, a composition containing the chalcone compounds can be prepared according to a conventional method and may be formulated alone or in combination with pharmaceutically acceptable carriers, excipients, diluents and so on, to prepare formulations, such as powders, granules, tablets, capsules, injections, and the like. Also, these compounds may be formulated unit dosage formulations or multiple dosage formulations for oral or parenteral administration, such that they can be used as therapeutic agents having IL-5 inhibitory effects.
[33] Hereinafter, the present invention will be described in further detail with reference to examples. It is to be understood, however, that these examples are only examples for clearly describing the preparation method of the present invention, and the scope of the present invention is not limited thereto. Also, those skilled in the art will appreciate that various conditions in the examples can be changed within a reasonable range, and such changes will be included in the technical idea of the present invention.
[34] Examples
[35] Is) Preparation of chalcone derivatives
[36] Example 1 : (Eyi-^-cvclohexylmethoxy-ό-hvdroxyphenviyS-phenylpropenone
[37] 0.116 g (0.47 mmol) of 2-cyclohexylmethoxy-6-hydroxyacetophenone was dissolved in 10 ml of a solvent obtained by dissolving sodium hydroxide in 90% ethyl alcohol at a concentration of 8.7%. 0.050 g (0.47 mmol) of benzaldehyde was added thereto and the solution was stirred at 40-50 0C for 12 hours. The reaction solution was concentrated under reduced pressure to remove the solvent, and the remaining material was added to 30 D of distilled water, acidified with 10 D of 2N hydrochloric acid aqueous solution and then dissolved in dichloromethane. The dichloromethane layer was separated, dried with anhydrous sodium sulfate and concentrated under reduced pressure, thus obtaining a crude product. The crude product was separated and purified by column chromatography, thus obtaining 0.091 g of compound 1 (Table 1).
[38] 58 % yield ; orange crystal ; mp = 94-96 0C; Rf = 0.29 (hexanes : ethyl acetate = 10
: 1), IR (KBr) 3400, 3100, 2950, 1640 Cm 1 NMR (CDCl3) δ 1.01-1.89 (m, HH), 3.84 (d, 2H, J = 6.0 D), 6.39 (d, IH, J = 8.0 D), 6,59 (d, IH, J = 8.4 D), 7.32 (t, IH, J = 8.4 D), 7.39-7.41 (m, 3H), 7.59-7.61 (m, 2H), 7.79 (d, IH, J = 15.6 D), 7.94 (d, IH, J = 15.6 D), 13.07 (s, IH).
[39] Example 2 : Methyl
(E)-4-[3-(2-cvclohexylmethoxy-6-hvdroxyphenyl)-3-oxopropene-l-yllbenzoate
[40] 0.5 g (1.3 mmol) of
(E)-4-[3-(2-cyclohexylmethoxy-6-hydroxyphenyl)-3-oxoprop-l-enyl]benzoic acid was dissolved in 250 ml of MeOH with heating at 60 0C. Then, the solution was stirred for 1 hours while 2 ml of sulfuric acid was slowly added dropwise thereto. Then, the stirred solution was distilled under reduced pressure to remove MeOH, and the remaining material was diluted in 50 ml of dichloromethane and then washed several times with water. The organic layer was separated, dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated and purified by flash column chromatography, thus obtaining 0.2 g of compound 2 (Table 1).
[41] 40 % yield ; deep yellow crystal; mp = 118-119 0C; Rf = 0.22 (hexanes : ethylacetate = 8 : 1), IR (KBr) 3450, 3100, 2950, 1720, 1610 cm"1 NMR (CDCl3) δ 1.04-1.88 (m, HH), 3.86 (d, 2H, J = 5.6 D), 3.95 (s, 3H), 6.40 (d, IH, J = 8.4 D), 6.60 (d, IH, J = 6.4 D), 7.34 (t, IH, J = 8.4 D), 7.65 (d, 2H, J = 8.4 D), 7.77 (d, IH, J = 15.6 D), 7.98 (d, IH, J = 15.6 D), 8.07 (d, 2H, J = 8.4 D), 13.07 (s, IH).
[42] Example 3 : (Εs)-3-(4-chlorophenyls)-l-(2-cvclohexylmethoxy-6-hvdroxyphenyls)propenone
[43] Under the same conditions as in Example 1, 1 g (4 mmol) of
2-cyclohexylmethoxy-6-hydroxyacetophenone was condensed with 1.14 g (8 mmol) of 4-chlorobenzaldehyde, thus preparing 0.8 g of compound 3 (Table 1).
[44] 53.7 % yield ; mp = 120-122 0C; deep orange crystal; Rf = 0.29 (hexanes : ethyl acetate = 10 : 1); IR (KBr) 3400, 3100, 2950, 1640 cm"1 NMR (CDCl ) δ 1.01-1.88 (m, 1 IH), 3.85 (d, 2H, J = 6.0 D), 6.39 (d, IH, J = 8.4 D), 6.59 (d, IH, J = 8.4 D), 7.33 (t, IH, J = 8.4 D), 7.37 (d, 2H, J = 8.4 D), 7.52 (d, 2H, J = 8.4 D), 7.72 (d, IH, J = 15.6 D), 7.09 (d, IH, J = 15.6 D), 13.05 (s, IH).
[45] Example 4 : N-
(ΕV4-r3-(2-cyclohexylmethoxy-6-hydroxyphenylV3-oxopropene-l-yllphenyl acetamide
[46] Under the same conditions as in Example 1, 3 g (4 mmol) of
2-cyclohexylmethoxy-6-hydroxyacetophenone was condensed with 2 g (12 mmol) of 4-acetamidobenzaldehyde, thus preparing 3.0 g of compound 4 (Table 1).
[47] 64 % yield; yellow crystal; mp=203~205 0C; Rf = 0.21 (hexanes : ethyl acetate = 6 :
1); IR (KBr) 3300, 3100, 2950, 1680 cm"1 NMR (CDCl3) δ 1.05-1.89 (m, HH), 2.21 (s, 3H), 3.85 (d, 2H, J = 6.0 D), 6.39 (d, IH, J = 8.4 D), 6.58 (d, IH, J = 8.4 D), 7.32 (t, IH, J = 8.4 D), 7.44 (s, IH), 7.56 (m, 4H), 7.75 (d, IH, J = 15.6 D), 7.88 (d, IH, 15.6 D), 13.07 (s, IH).
[48] Example 5 :
(E)-l-(2-cvclohexylmethoxy-6-hvdroxyphenyl)-3-(4-ethylphenyl)propenone
[49] Under the same conditions as in Example 1, 2 g (8.1 mmol) of
4-cyclohexylmethoxy-6-hydroxyacetophenone was condensed with 0.87 g (8.2 mmol) of 4-ethylbenzaldehyde, thus preparing 2 g of compound 5 (Table 1).
[50] 69 % yield; orange crystal; mp = 81-83 0C; Rf = 0.29 (hexanes : ethyl acetate = 10
: 1); IR (KBr) 3100, 2950, 1640 cm"1 NMR (CDCl ) 1.03-1.27 (m, 8H), 1.66 (t, 3H, J = 7.6 D), 1.88 (m, 3H), 2.68 (q, 2H, J = 7.6 D), 3.85 (d, 2H, J = 5.6 D), 6.39 (d, IH, J = 8.4 D), 6.58 (d, IH, J = 8.4 D), 7.22 (d, 2H, J = 8.0 D), 7.31 (t, IH, J = 8.4 D), 7.52 (d, 2H, J = 8.0 D), 7.79 (d, IH, J = 15.6 D), 7.91 (d, IH, J = 15.6 D), 13.07 (s, IH).
[51] Example 6 :
CEV 1 -(^-cyclohexylmethoxy-ό-hydroxyphenylV 3- r4-(hydroxymethyls)phenyllpropenon e
[52] Under the same conditions as in Example 1, 0.2 g (0.81 mmol) of
4-cyclohexylmethoxy-6-hydroxyacetophenone was condensed with 0.136 g (2.42 mmol) of 4-hydroxymethylbenzaldehyde, thus preparing 0.2 g of compound 6 (Table
1). [53] 66 % yield; orange crystal; mp = 93 0C; Rf = 0.45 (hexanes : ethyl acetate = 2 : 1), IR (KBr) 3300, 3100, 2930, 2850, 1640 cm"1 NMR (CDCl ) 1.08-1.89 (m, HH), 3.87 (d, 2H, J = 6.0 D), 4.75 (s, 2H), 6.39 (d, IH, J = 8.4 Hz), 6.59 (d, IH, J = 8.4 Hz), 7.33 (t, IH, J=8.4 Hz), 7.40 (d, 2H, J = 8.0 Hz), 7.59 (d, 2H, J = 8.0 Hz), 7.79 (d, IH, J = 15.6 Hz), 7.95 (d, IH, J = 15.6 Hz), 13.20 (s, IH).
[54] Example 7: (E)-4-r3-(2-cvclohexylmethoxy-6-hvdroxyphenyl)-3-oxopropene-l-yll benzaldehvde
[55] Under the same conditions as in Example 1, 0.126 g (0.5 mmol) of
4-cyclohexylmethoxy-6-hydroxyacetophenone was condensed with 0.068 g (0.5 mmol) of terephthalaldehyde, thus preparing 1.11 g of compound 7 (Table 1).
[56] 60 % yield; red crystal; mp = 116-118 0C; Rf = 0.19 (hexanes : ethyl acetate = 8 :
1), IR (KBr) 3450, 3100, 2950, 1700, 1640 cm"1 NMR (CDCl ) 1.00-1.87 (m, HH), 3.86 (d, 2H, J = 6.0 D), 6.40 (d, IH, J = 8.4 D), 6.60 (d, IH, J = 8.4 D), 7.36 (t, IH, J = 8.4 D), 7.74 (d, 2H, J = 8.4 D), 7.77 (d, IH, J = 15.6 D), 7.92 (d, 2H, J = 8.4 D), 8.01 (d, IH, J = 15.6 D), 10.04 (s, IH), 13.05 (s, IH).
[57] Example 8 : (ΕV4-r3-(2-cyclohexylmethoxy-6-hydroxyphenylV3-oxopropene-l-yll bezensulfonamide
[58] Under the same conditions as in Example l, 0.10 g (0.4 mmol) of
4-cyclohexylmethoxy-6-hydroxyacetophenone was condensed with 0.075 g (0.41 mmol) of formylbenzenesulfonamide, thus preparing 0.092 of compound 8 (Table 1).
[59] 56 % yield; deep yellow crystal; mp = 130 0C; Rf = 0.33 (hexanes : ethyl acetate =
23 : 1); IR (KBr) 3400, 3330, 3100, 2950, 1640 cm"1 NMR (DMSO-d ) 1.03-1.87 (m, 1 IH), 3.79 (d, 2H, J = 5.6 D), 6.53 (d, IH, J = 8.0 D) ,6.56 (d, IH, J = 8.4 D), 7.26 (t, IHJ = 8.4 D) 7.39 (d, 2H, J = 6.4 D), 7.45 (s, 2H), 7.82-7.88 (m, 4H), 10.63(s, IH).
[60] Example 9 : (E)-4-[3-(2-benzyloxy-6-hvdroxyphenyl)-3-oxopropene-l-yll benzene- sulfonamide
[61] Under the same conditions as in Example l, 0.10 g (0.41 mmol) of
4-benzyloxy-6-hydroxyacetophenone was condensed with 0.076 g (0.41 mmol) of formylbenzenesulfonamide, thus preparing 0.087 g of compound 9 (Table 1).
[62] 52 % yield; deep yellow crystal; mp = 182-183 0C; Rf = 0.33(hexanes : ethyl acetate
= 2 : 1); IR (KBr) 3400, 3330, 3100, 1640 cm"1 NMR (DMSO-d ) 5.13(s, 2H), 6.57 (d, IH, J = 8.4 D), 6.68 (d, IH, J = 8.4 D), 7.26 (t, IHJ = 8.4 D), 7.36 (d, 2H, J = 8.4 D), 7.44-7.72 (m, 7H), 7.78 (d, IH, J = 15.6 D), 7.82 (d, IH, J = 15.6 D), 10.65 (s, IH).
[63] Example 10 : N-(ΕV4-r3-(2.6-dimethoxyphenylV3-oxopropene-l-yllphenyl acetamide
[64] Under the same conditions as in Example 1, 1 g (5.54 mmol) of
2,6-dimethoxyacetophenone was condensed with 1.08 g (6.65 mmol) of 4-acetamidobenzaldehyde, thus preparing 1.20 g of compound 10 (Table 1).
[65] 67 % yield; yellow ocher crystal; mp = 221-222 0C; Rf = 0.15 (hexanes : ethyl acetate = 1 : 2); IR (KBr) 3390, 3050. 2950, 1700, 1650 cm"1 NMR (Acetone-d ) 2.09 (s, 3H), 3.77 (s, 6H), 6.74 (d, 2H, J = 8.4 D), 6.85 (d, IH, J = 16.4 D), 7.20 (d, IH, J = 16.4 D), 7.38 (t, IH, J = 8.4 D), 7.58 (d, 2H, J = 8.8 D), 7.71 (d, 2H, J = 8.8 D).
[66] Example 11 : (Ε)-l-(2.6-dimethoxyphenyl)-3-(4-ethylphenyl)propenone
[67] Under the same conditions as in Example 1, 0.5 g (2.77 mmol) of
2,6-dimethoxyacetophenone was condensed with 0.45 g (3.32 mmol) of 4-ethylbenzaldehyde, thus preparing 0.62 g of compound 11 (Table 1).
[68] 75 % yield; pale yellow crystal; mp = 55-57 0C; Rf = 0.10 (hexanes : ethyl acetate
= 10 : 1); IR (KBr) 3050, 2950, 1650 cm"1 NMR (Acetone-d ) 1.20 (t, 3H, J = 7.6 D), 2.64 (q, 2H, J = 7.6 D), 3.74 (s, 6H), 6.72 (d, 2H, J = 8.4 D), 6.90 (d, IH, J = 16.4 D), 7.24 (d, IH, J = 16.4 D), 7.25 (d, 2H, J = 8.0 D), 7.26 (t, IH, J = 8.4 D), 7.52 (d, 2H, J = 8.0 D).
[69] Example 12: (EV l-(2.6-dimethoxyphenylV3-r4-(hydroxymethyls)phenyllpropenone
[70] Under the same conditions as in Example 1, 0.26 g (1.44 mmol) of
2,6-dimethoxyacetophenone was condensed with 0.2 g (1.41 mmol) of 4-hydroxymethylbenzaldehyde, thus preparing 0.30 g of compound 12 (Table 1).
[71] 70 % yield; yellow liquid; Rf = 0.14 (hexanes : ethyl acetate = 1 : 1); IR (film)
3450(OH), 3150(Alkene), 2950(Alkane), 1630(C=O), 1600(Ar), 1240(C-O), NMR(CDCl3) =2.57(s, IH), 3.76(s, 6H), 4.68(s, 2H), 6.60(d, 2H, J=8.0D), 6.91(d, IH, J=16.4D), 7.29(d, 2H, J=8.0D), 7.33(t, IH, J=8.0D), 7.34(d, 2H, J=8.0D), 7.47(d, 2H, J=8.0D).
[72] Example 13: (E)-4-[3-(2.6-dimethoxyphenyl)-3-oxopropene-l-yll benzene- sulfonamide
[73] Under the same conditions as in Example 1, 0.1 g (0.56 mmol) of
2,6-dimethoxyacetophenone was condensed with 0.95 g (1.70 mmol) of 4-formylbenzenesulfonamide, thus preparing 0.12 g of compound 13 (Table 1).
[74] 62 % yield; yellow crystal; mp = 180-181 0C; Rf = 0.33(hexanes : ethyl acetate = 3 :
1); IR (KBr) 3420, 3200, 2950, 1650 cm"1 NMR (CDCl3) 3.78 (s, 6H), 6.63 (d, 2H, J = 8.4 D), 7.01 (d, IH, J = 16.4 D), 7.34 (d, IH, J = 16.4 D), 7.36 (t, IH, J = 8.4 D), 7.64 (d, 2H, J = 8.4 D), 7.92 (d, 2H, J = 8.4 D).
[75] Example 14: (E)- l-(2.6-dimethoxyphenyl)-3-(4-nitrophenyl)propenone
[76] Under the same conditions as in Example 1, 3 g (17 mmol) of
2,6-dimethoxyacetophenone was condensed with 2.5 g (17 mmol) of 4-nitrobenzaldehyde, thus preparing 4.03 g of compound 14 (Table 1).
[77] 77 % yield ; yellow crystal; mp = 164-166 0C; Rf = 0.18 (hexanes : ethyl acetate =
3 : 1); IR (KBr) 3100, 2950, 1690 cm"1 NMR (CDCl3) 3.80 (s, 6H), 6.63 (d, 2H, J = 8.4 D), 7.05 (d, IH, J = 16.0 D), 7.36 (t, IH, J = 8.4 D), 7.38 (d, IH, J = 16.0 D), 7.67 (d, 2H, J = 8.8 D), 8.22 (d, 2H, J = 8.8 D).
[78] Example 15: (ΕV3-(4-chlorophenylV l-^.ό-diethoxyphenyDpropenone [79] Under the same conditions as in Example 1, 0.1 g (0.56 mmol) of
2,6-diethoxyacetophenone was condensed with 0.072 g (0.56 mmol) of 4-chlorobenzaldehyde, thus preparing 0.089 g of compound 15 (Table 1).
[80] 48 % yield ; pale yellow crystal; mp = 92 0C; Rf = 0.35 (hexanes : ethyl acetate = 6
: 1), IR (KBr) 3100, 2950, 1690 cm"1 NMR (CDCl ) 1.33 (t, 6H, J = 8.4 D), 4.04 (q, 4H, J = 8.4 D), 6.57 (d, 2H, J = 8.4 D), 6.92 (d, IH, J = 16.0 D), 7.26 (d, IH, J = 16.0 D), 7.28 (t, IH, J = 8.6 D), 7.34 (d, 2H, J = 8.4 D), 7.45 (d, 2H, J = 8.4 D).
[81] Example 16: N-(E)-4-[3-(2.6-diethoxyphenyl)-3-oxopropne-l-yllphenyl acetamide
[82] Under the same conditions as in Example 1, 0.5 g (2.57 mmol) of
2,6-diethoxyacetophenone was condensed with 0.42 g (8.02 mmol) of 4-acetamidobenzaldehyde, thus preparing 0.535 g of compound 16 (Table 1).
[83] 59 % yield ; deep yellow crystal; mp = 175 0C; Rf = 0.23 (hexanes : ethyl acetate =
1 : 1); IR (KBr) 3390, 3050. 2950, 1700 cm"1 NMR (CDCl ) 1.33 (t, 6H, J=8.4 D), 2.19 (s, 3H), 4.04 (q, 4H, J = 8.4 D), 6.57 (d, 2H, J = 8.4 D), 6.88 (d, IH, J = 16.0 D), 7.25 (d, IH, J = 16.0 D), 7.27 (t, IH, J = 8.4 D), 7.41 (s, IH), 7.47 (d, 2H, J = 8.8 D), 7.54 (d, 2H, J = 8.8 D).
[84] Example 17: (ΕV4-r3-(2.6-diethoxyphenylV3-oxopropen- l-yDbenzenesulfonamide
[85] Under the same conditions as in Example 1, 0.1 g (0.56 mmol) of
2,6-diethoxyacetophenone was condensed with 0.095 g (1.70 mmol) of 4-formylbenzenesulfonamide, thus preparing 0.13 g of compound 17 (Table 1).
[86] 62 % yield ; yellow crystal; mp = 62 0C; Rf = 0.33 (hexanes : ethyl acetate = 3 : 1);
IR (KBr) 3420, 3200, 2950, 1650 cm"1 NMR (CDCl ) 1.33 (t, 6H, J = 8.4 D), 4.04 (q, 4H, J = 8.4 D), 4.91 (s, 2H), 6.59 (d, 2H, J = 8.4 D), 7.02 (d, IH, J = 16.0 D), 7.29 (t, IH, J = 8.4 D), 7.34 (d, IH, J = 16.0 D), 7.65 (d, 2H, J = 8.4 D), 7.93 (d, 2H, J = 8.4 D).
[87] Example 18: (E)-l-(2.6-diethoxyphenyl)-3-(4-nitrophenyl)propenone
[88] Under the same conditions as in Example 1, 0.1 g (0.56 mmol) of
2,6-diethoxyacetophenone was condensed with 0.095 g (0.56 mmol) of 4-nitrobenzaldehyde, thus preparing 0.126 g of compound 18 (Table 1).
[89] 66 % yield ; yellow crystal; mp = 108 0C; Rf = 0.44 (hexanes : ethyl acetate = 6 :
1); IR (KBr) 3100, 2950, 1690 cm"1 NMR (CDCl ) 1.33 (t, 6H, J = 8.4 D), 4.04 (q, 4H, J = 8.4 D), 6.59 (d, 2H, J = 8.4 D), 7.05 (d, IH, J = 16.0 D), 7.30 (t, IH, J = 8.4 D), 7.37 (d, IH, J = 16.0 D), 7.67 (d, 2H, J = 8.8 D), 8.23 (d, 2H,J = 8.8 D).
[90] Example 19: (ΕVl-(2.6-diethoxyphenylV3-phenylpropenone
[91] Under the same conditions as in Example 1, 0.1 g (0.56 mmol) of
2,6-diethoxyacetophenone was condensed with 0.080 g (1.43 mmol) of benzaldehyde, thus preparing 0.129 g of compound 19 (Table 1).
[92] 78 % yield ; pale yellow crystal; mp = 71-72 0C; Rf = 0.32 (hexanes : ethyl acetate
= 7 : 1); IR (KBr) 3100, 2970, 1650 cm"1 NMR (CDCl3) 1.33 (t, 6H, J = 8.4 D), 4.04(q, 4H, J = 8.4 D), 6.56 (d, 2H, J = 8.4 D), 6.96 (d, IH, J = 16.0 D), 7.28 (t, IH, J = 8.3 D), 7.31 (d, IH, J = 16.0 D), 7.37 (m, 3H), 7.52 (m, 2H).
[93] Example 20: (E)-4-[3-(2A6-trimethoxyphenyl)-3-oxopropen-l-yll benzene - sulfonamide
[94] Under the same conditions as in Example 1, 0.1 g (0.48 mmol) of
2,4,6-trimethoxyacetophenone was condensed with 0.088 g (0.48 mmol) of 4-formylbenzenesulfonamide, thus preparing 0.144 g of compound 20 (Table 1).
[95] 80 % yield ; pale yellow crystal; mp = 65 0C; Rf = 0.18 (hexanes : ethyl acetate = 2
: 1); IR (KBr) 3420, 3100, 2950, 1650 cm"1 NMR (CDCl ) 3.78 (s, 6H), 3.87 (s, 3H), 6.16 (s, 2H), 7.01 (d, IH, J = 16.0 D), 7.37 (d, IH, J = 16.0 D), 7.61 (d, 2H, J = 8.4 D), 7.89 (d, 2H, J = 8.4 D).
[96] Example 21 : (EV l-(7 Aό-trimethoxyphenyiyS-^-nitrophenyPpropenone
[97] Under the same conditions as in Example 1, 0.1 g (0.48 mmol) of
2,4,6-trimethoxyacetophenone was condensed with 0.072 g (0.48 mmol) of 4-nitrobenzaldehyde, thus preparing 0.131 g of compound 21 (Table 1).
[98] 80 % yield ; pale yellow crystal; mp = 163-164 0C; Rf = 0.35 (hexanes : ethyl acetate = 4 : 1); IR (KBr) 3100, 2950, 1690 cm"1 NMR (CDCl3) 3.78 (s, 6H), 3.87 (s, 3H), 6.17 (s 2H), 7.07 (d, IH, J = 16.0 D), 7.44 (d, IH, J = 16.0 D), 7.67 (d, 2H, J = 8.8 D), 8.23 (d, 2H, J = 8.8 D).
[99] Example 22: (EV l-^.ό-dichlorophenylVS-tAnitrophenyDpropenone
[100] Under the same conditions as in Example 1, 0.2 g (1.05 mmol) of
2,6-dichloroacetophenone was condensed with 0.19 g (1.2 mmol) of 4-nitrobenzaldehyde, thus preparing 0.131 g of compound 22 (Table 1).
[101] 38 % yield ; pale yellow crystal; mp = 145-146 0C; Rf = 0.18 (hexanes : ethyl acetate = 8 : 1); IR (KBr) 3100, 2950, 1690 cm"1 NMR (CDCl ) 7.04(d, IH, J = 16.0 D), 7.29 (d, IH, J = 16.0 D), 7.35-7.41 (m, 3H), 7.70 (d, 2H, J = 8.0 D), 8.26 (d, 2H, J = 8.0 D).
[102] Example 23: (E)-4-[3-(2.6-dichlorophenyl)-3-oxopropene-l-yllbenzensulfonamide
[103] Under the same conditions as in Example 1, 0.1 g (0.56 mmol) of
2,6-dichloroacetophenone was condensed with 0.103 g (0.56 mmol) of 4-formylbenzenesulfonamide, thus preparing 0.078 g of compound 23 (Table 1).
[104] 42 % yield ; pale yellow crystal; mp = 141-142 0C; Rf = 0.33 (hexanes : ethyl acetate = 3 : 1); IR (KBr) 3420, 3100, 2950, 1650 cm"1 NMR (CDCl ) 7.22 (d, IH, J = 16.0 D), 7.39 (d, IH, J = 16.0 D), 7.54-7.62 (m, 3H), 7.86 (d, 2H, J = 8.0 D), 7.92 (d, 2H, J = 8.0 D).
[105] 2) Measurement of IL- 5 inhibitory effects
[106] (1) Dissolution and dilution of samples
[107] Each of the samples of the chalcone compounds prepared in Examples 1 to 23 was dissolved in 100% DMSO to a concentration of 100 mg/D.
[108] (2) Subculture of cell line Y16
[109] Y16 cells used in the experiment are floating cells that proliferate in media. The
Y16 cells were diluted in RPMI- 8% FBS medium to a cell concentration of 1 x 10 cells/D, and 1 ml of the medium was dispensed into a Petri dish. Then, 9 D of RPMI- 8% FBS medium and 5 U/D of mIL-5 were added thereto, and then the mixture was cultured in 5% CO at 37 0C for 48 hours. The culture medium was centrifuged at 4 0C and 1500 rpm to precipitate the cells, and the cells were suspended in 1 D of medium, stained with trypan blue and then counted.
[110] (3) Measurement of mIL-5-dependent Y16 cell proliferation
[111] 100 D of Y16 cells were dispensed into each well of a 96- well microplate at a cell density of 1 x 10 cells. 100 units of mIL-5 was diluted 3-fold serially to 0.003 units, and 100 D of each of the dilutions was added to each well of the 96- well plate, followed by culturing in 5% CO at 37 0C for 48 hours. After 48 hours, 20 D of WST-I solution was added to each well of the above plate and incubated in 5% CO at 37 0C for 3-4 hours. Then, the absorbance at 450 nm was measured with a microplate reader using a 690nm wavelength as a control.
[112] (4) Assay of mIL-5 inhibition of samples
[113] The mIL-5 inhibitory effects of the samples were assessed based on the mlL-
5-dependent proliferation of Y16 cells.
[114] Y16 cells were dispensed into each well of a 96- well microplate at a cell concentration of 1 x 10 cells/D, and 50 D of mIL-5 and 50 D of each sample were added to each well. Herein, mIL-5 and the sample solutions were diluted in RPMI-8% FBS medium before use, and in a control A group, medium was added instead of the sample. In a control B group, medium was added instead of IL-5 and the sample. The cell media thus prepared were cultured in the same conditions as in the above section 3), and then measured for absorbance.
[115] The IL-5 inhibitory effects (%) of the samples at a concentration of 50 μM were calculated according to the following equation, and the calculation results are shown in Table 1 together with IC values.
50
[116] sam ple45o - control A450 inh ibitory effects (% ) = ( 1 ) x 1 00 control B450 - control A450
[117] sample : absorbance at 450nm of sample group
[118] control A 450 : absorbance at 450nm of control A g σrouxp-
[119] control B 450 : absorbance at 450nm of control B g orourp [121] [table 1] [122]
Figure imgf000013_0001
Figure imgf000013_0002
[123]
Industrial Applicability [124] As described above, the novel chalcone derivatives according to the present invention will be useful as asthma control agents for alleviating asthma symptoms, inflammation inhibitors, and allergy inhibitors having no nonspecific response to proteins.
[125]

Claims

Claims [1] Chalcone derivatives represented by Formula 1:
[formula 1]
Figure imgf000015_0001
wherein, R is benzyl, cyclohexylmethyl, hydrogen, methyl or ethyl, R is benzyl, cyclohexylmethyl, hydrogen, methyl or ethyl, R is methoxy or hydrogen, R is Cl, -NHCOCH , -COOCH , CH OH, -CHO, -SO NH , -NO , or -COOH, R is
3 3 2 2 2 2 4 not -COOH if R is benzyl, cyclohexylmethyl, hydrogen, R and R are hydrogen.
[2] A method for preparing chalcone derivatives of Formula 1 set forth in Claim 1, the method comprising condensing a compound (A) with a compound (B) in an alcohol solvent in the presence of a base according to a reaction pathway shown in Reaction Scheme 1 : [Scheme 1]
Figure imgf000015_0002
(A) (B) wherein, R is benzyl, cyclohexylmethyl, hydrogen, methyl or ethyl, R is benzyl, cyclohexylmethyl, hydrogen, methyl or ethyl, R is methoxy or hydrogen, R is Cl, -NHCOCH 3 , -COOCH 3 , CH 2 OH, -CHO, -SO 2 NH 2 , -NO 2 , or -COOH, R 4 is not -COOH if R is benzyl, cyclohexylmethyl, hydrogen, R and R are hydrogen.
[3] A composition for treating chronic allergic diseases, which comprises, as active ingredients, chalcone derivatives of Formula 1 set forth in Claim 1.
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Publication number Priority date Publication date Assignee Title
EP2678305A4 (en) * 2011-02-25 2015-11-04 Univ Johns Hopkins Chalcone derivatives as nrf2 activators

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